Vigorous physical activity and atrial fibrillation in healthy individuals: What is the correct approach?

Abstract Sport activity compared to sedentary life is associated with improved wellbeing and risk reduction in many different health conditions including atrial fibrillation (AF). Vigorous physical activity is associated with increased AF risk. We describe four individuals, who regularly perform endurance sport activity and developed AF. We discuss the changes occurring in the heart of endurance athletes and the possible etiology for AF, as well as currently available treatment options in this seemingly healthy population. Although the etiology of AF in the general population differs from the one in the usually younger endurance sport activity population, the treatment options are similar. There are several factors unique to those involved in vigorous physical activity that can influence their management. Despite a lack of evidence, endurance athletes with AF have traditionally been advised to “de‐training,” to reduce both the amount and intensity of exercise. Some of the current offered treatment options (beta‐blockers, class III antiarrhythmic) have a varied range of adverse effect, hindering them unattractive for these individuals. Depending on risk stratification tools, anticoagulation may be indicated. Some suggest an intermittent dosing therapy, while others recommend following current guidelines. AF ablation is recommended in exercising individuals with recurrent, symptomatic AF and/or in those who do not want drug therapy, given its impact on athletic performance, AF treatment decisions should be individualized for those engaging vigorous physical activity, while considering the potential risks, the urgency of returning to training, and the will and expectations of the patient.


| CASE 1
A 51-year old male, past national champion in shot put and javelin throw, continued after retirement from athletics, to practice endurance sport activities as canoeing and field jogging.He used to practice on a daily basis at least 1 h a day.He started feeling palpitations and described his pulse as irregular.Baseline ECG was normal.A 24-h ECG Holter monitor recorded at rest paroxysmal episodes of AF at a ventricular rate of 130 per minute.Echocardiography revealed normal heart function, no major valvular problems, a septal thickness of 14 mm and posterior wall of 12 mm, and a normal size left atrium.Stress test was normal without any arrhythmias.He was prescribed to take Propafenone if AF recurs ["Pill in the pocket" approach] and was advised to decrease physical activity.His CHA 2 DS 2 VASc score was 0. However, only a month later, when he had a prolonged AF episode that lasted for several hours, he stopped his vigorous daily sport activity.Since he reduced his physical activity to twice a week, he did not report feeling palpitations, and 24-h ECG Holter monitor revealed only normal sinus rhythm with long periods of bradycardia.He did not use any medications.

| CASE 2
A 48-year old male was admitted to the hospital with a minor stroke.
He was an ironman athlete with a BMI of 25 and only 3% of fat in his body.He practiced every day between 2 and 3 h of vigorous sport activity, whether running, swimming, cycling or a combination of these.ECG revealed AF.Based on brain CT findings, and the rapid clinical neurological improvement, no mechanical intervention or thrombolytic therapy was done.The neurological findings resolved within a few days.Trans Esophageal Echocardiography did not reveal a patent forman ovale, there was no plaque in the aorta and no thrombus in the left atrium or the left atrial appendage.His left atrium was mildly dilated, and there was mild hypertrophy of the LV walls.He was successfully cardioverted to normal sinus rhythm.Due to the stroke, direct oral anticoagulants (DOACs) were started.
When discussed future recommendations regarding his ironman activity, he insisted he wants to continue.Several weeks later he underwent AF ablation with pulmonary vein isolation.He currently continues to take DOACs, continues to practice sport activity, though with a lower heart rate target and somewhat less vigorous.No AF episodes were recorded in his Apple watch nor in several 24-h ECG Holter monitor recordings.

| CASE 3
A 48-year old male, bodybuilder, nonsmoker, with Thalassemia minor, was admitted with complaints of weakness, sweating, gastrointestinal distress, vomiting and hypertension.On admission he had AF.An old ECG recording showed AF also 5 years prior.As part of his bodybuilding professional career, he had been using substances as anabolic steroids and growth hormone, alongside the consumption of protein enriched food supplements.Every day he trained and practiced weight lifting for almost 2-h.
CT scan of the aorta and its branches showed mild atherosclerotic changes.Echocardiogram revealed a severe decrease of left ventricular function [<30%], all chambers of the heart showed a mild enlargement, alongside a mild to moderate mitral insufficiency, mild aortic insufficiency, severe tricuspid insufficiency and a pulmonary hypertension estimated to be 50 mmHg.He underwent coronary angiography that found no coronary artery narrowings.
He was started with DOACs and heart failure medications.
Possible treatment options were discussed.Mainly due to the decrease LV function-he underwent successful AF ablation several weeks after the first admission.On follow up he had no symptoms, he is still on sinus rhythm, continues to take his DOAC and heart failure treatment alongside his anabolic steroids and growth hormone, which he refused to stop.His LVEF improved to 45%, and his valvular as well as pulmonary artery pressure parameters showed significant improvements as well.

| CASE 4
A 56-year old, who used to work as a running group trainer and participated in several full and half marathon runs in the past few years, was admitted with anginal chest pain and AF with rapid ventricular response.Of note, just before his hospitalization, he stopped his vigorous endurance activities due to rupture of knee

| DISCUSSION
We report a case series of otherwise healthy individuals practicing vigorous sport activity for prolonged periods, all with AF.Cardiac arrhythmias in athletes represent a major challenge.Ventricular arrhythmias and sudden cardiac death in young athletes have been the main focus of research and discussions in this field.,23 The benefits of moderate physical activity in controlling cardiovascular risk factors and in reducing the risk of AF have been widely demonstrated.Still, some concerns have been raised about the potential adverse effects of vigorous physical activity, particularly regarding the risk of arrhythmias in the apparently fit endurance athletes.6][27][28] A recent very large cohort study showed an apparent "dose-response" curve indicating that the very fittest athletes and those who performed exercise for many years were at the highest risk for AF. 29 A frequent question that is asked is whether sports are healthy?
It is well known that endurance athletes remain at lower cardiovascular risk and experience fewer strokes. 1 There is a complex relationship between exercise and AF.Based on the current available data, it is reasonable to conclude that maintaining an active and fit lifestyle reduces the risk of AF.However, these benefits do not seem to extend to those practicing endurance exercise far beyond the recommended volume in current guidelines. 30 remains unclear at which point exercise may become detrimental.
A recent perspective document from the American College of Cardiology's Sports and Exercise Cardiology Leadership Council reported that the "optimal" exercise dose to reduce the risk for cardiovascular events was established at 41 metabolic equivalents of task (MET)-hour/ week, that is 9.1 h/week of moderate-intensity exercise. 9The current consensus is that moderate exercise-reduces AF risk; whereas intense strenuous exercise may increase AF burden. 14durance sports such as cross country skiing, orienteering, marathon running and cycling were associated with increased risk for AF, 31 while there is currently no evidence that non-endurance athletes are also at risk for AF.The reason may be, at least partly, due to the fact that endurance sports requires far greater levels of physical training and conditioning, for longer time proportions, leading to greater hemodynamic stress placed on the heart. 32 is more prevalent in endurance athletes, especially in middle aged and older male athletes and those who competed at a young age.However, the impact of female sex on AF risk among athletes has been sparsely studied.Although available data suggests female athletes may exhibit lower risk of AF, the limited number of women participants in exercise studies, hinders the ability to draw firm conclusions. 21,29,33,34e available data suggest a U-shaped relationship between exercise dose and AF risk (Figure 1). 14Not only that, according to the latest European Society of Cardiology (ESC) guidelines, counseling and a warning is advised regarding the possible effects of longlasting, high-intensity sports activity on AF risk, especially in middleaged men. 1 The ESC document states the following: "Physical activity should be considered to help prevent AF incidence or recurrence, with the exception of excessive endurance exercise, which may promote AF.Moderate regular physical activity is recommended to prevent AF, while athletes should be counseled that long-lasting intense sports participation can promote AF."

| ENDURANCE SPORT AND ANATOMICAL CHANGES IN THE HEART
There is data that imply that high volumes of chronic endurance exercise training may be detrimental for the heart structures.Crosssectional studies have reported that the most active veteran endurance runners have not only more AF 16 but also an increased risk for myocardial fibrosis 35,36 and coronary artery calcification (CAC). 18Hou et al. 37 reported that the most active athletes had a higher CAC prevalence compared to the least active athletes (68% vs. 43%, OR: 3.2, 95% CI: 1.6-6.6).However, the most active athletes also had a lower prevalence of mixed plaques (48% vs. 69%; OR: 0.35, 95% F I G U R E 1 Conceptual overview of the "Extreme Exercise Hypothesis."Increasing volumes of exercise lead to a curvilinear decrease in health risks, but these health benefits may be partially lost once an individual performs exercise training beyond the optimal exercise dose. 12I: 0.15-0.85)and more often had only calcified plaques (38% vs. 16%; OR = 3.57; 95% CI: 1.28-9.97)compared with the least active athletes.This observation has important clinical relevance as mixed plaques are associated with a higher probability of future cardiovascular events compared with calcified plaques (38% vs. 6%). 14Subclinical and atherosclerotic coronary artery disease as well as structural cardiovascular abnormalities and arrhythmias are present in some of the most active veteran endurance athletes and need appropriate clinical followup to reduce the risk for adverse cardiovascular outcomes.Future studies are necessary in this population to establish the effects of these findings in veteran endurance athletes.

| PATHOPHYSIOLOGICAL CHANGES IN THE ENDURANCE ATHLETE LEADING TO AF
Several different physio-pathological mechanisms may explain the increased risk of arrhythmia in athletes. 38Coumel's triangle 39,40 still represents the clearest way of understanding the complex pathophysiological AF mechanism, identifying three important elements: [1] electrical and structural remodeling, [2] triggers and [3] the role of the autonomic nervous system.Cardiac adaptation to intense exercise results in increased vagal tone, lower resting heart rate and increased systolic output, ventricular dilation, and hypertrophy, all of which may cause a predisposition to AF recurrences. 13ditional pathophysiologic mechanisms may include recurrent fluid and electrolyte shifts (Table 1).
The left atrium plays a critical role in receiving pulmonary venous return and modulating left ventricular filling.With the onset of exercise, left atrial function contributes to the augmentation in stroke volume. 41Athletes are frequently observed to have enlarged left atrial size, when compared to non-athletes.The adaptation of the left atrium appears to be proportional to the cumulative volume of training over an individual's lifetime.The left atrial enlargement is attributed to the repetitive, volume and pressure overload applied during exercise, particularly that of long duration over many years, with some contribution from an expanded blood volume that is observed amongst the well-trained.Beyond the size of the left atrium, cross-sectional studies demonstrate a modest reduction in left atrial reservoir and contractile strain amongst athletes compared to sedentary controls. 41Structural and electrical changes within the atrium may also lead to a reduction in atrial refractoriness and therefore to conduction slowdown and electrical dispersion known to facilitate the formation of re-entry circuits and AF as a result.
The increased vagal tone in athletes further decreases the atrial refractory period, which could facilitate re-entry and predispose to AF, especially because it is associated with an intermittent-exerciserelated increase in sympathetic tone. 42Indeed, AF in athletes typically occur at rest and especially during sleep when the vagal tone is higher.Moreover, animal studies demonstrated an association between atrial enlargement, progressive atrial fibrosis, and inflammation due to intense exercise and their correlation with the risk of AF. 43 Of note, it seems that women are at a generally lower risk of developing AF than men because resting heart rate is usually higher, differences in vagal tone, smaller atria, and shorter P-wave duration, but these hypotheses are speculative and have not been demonstrated yet. 21,44

| TREATMENT
The treatment options for AF in endurance athletes are similar to those practiced in the general population. 45However, it must be remembered that the etiology of AF in the general population differs from the one in the usually younger endurance sport activity population.In the general population the patients are older with more traditional risk factors as hypertension, diabetes and coronary artery disease as a cause for AF.And indeed in the general population the CHA 2 DS 2 -VASc Score, that include the frequent AF etiologies, was verified and is well established. 1Yet, the AF etiology associated with sport, is related less to the classical risk factors and more to anatomical alterations and nervous system activation and no risk score was validated in this population.
There are several factors unique to athletes that can influence their management (Table 2).The avoidance of possible proarrhythmic substances such as alcohol 24 and certain medications, should be in conjugation with all treatments.Healthy diet and weight control counseling are also relevant in this population, as overweight and obesity, associated with increased AF risk, are nonnegligible among athletes. 46The clinical scenarios varies widely from asymptomatic patients to acute fatigue and exercise intolerance with the onset of AF.

| DETRAINING
The initial approach should be the recommendation of a reduction in physical activity, often referred to as detraining. 44,45This was the successful treatment of our patient #1.Importantly, the impact of altering ("athlete's heart") seems to be partially reversible by detraining. 47wever, data regarding the effects of training adaption on atrial remodeling and exercise-induced AF in humans do not exist. 48spite a lack of evidence, endurance athletes with AF have traditionally been advised to reduce both the amount and intensity of exercise.This approach assumes that the exercise stimulus plays a contributory role in the development of AF, and that continuation of the same stimulus could lead to further cardiac remodeling and ultimately disease progression.In an animal model, rats experienced increased AF inducibility after 16 weeks of endurance training on treadmill, with AF inducibility returning to baseline levels following 4 weeks of detraining. 13portantly, complete detraining is discouraged, as a relatively sedentary lifestyle is even more strongly associated with AF prevalence.Lifestyle modifications can become an unexpected obstacle, as many athletes with AF find physical activity to be part of their daily routine, a fact that can contribute to a failure of treatment.A designed randomized controlled trial to investigate the effects of training adaption in endurance athletes with paroxysmal AF is underway. 49

| MEDICATIONS
Medical therapy may be poorly tolerated.Achieving adequate rate control can be difficult due to the nature of endurance activity of these individuals.Beta-blockers are the reasonable choice but may not be tolerated due to their impact on physical performance. 1lcium-channel blockers and digitalis are usually not potent enough when used alone.Often a combination of individually titrated negatively chronotropic agents is needed, while avoiding sinus bradycardia at rest or chronotropic incompetence during exercise.
Rhythm control is equally complicated.Although it is generally preferable to heart rate control.Class III antiarrhythmic drugs are usually insufficient for control (sotalol) or relatively contraindicated in a young population (amiodarone).Amiodarone has long-term toxic effects such as pulmonary and hepatic toxicity, and it is therefore not recommended in younger, healthier populations, including athletes. 24is was the successful treatment of our patient #4.Flecainide and propafenone (class Ic) are effective for paroxysmal AF and acute cardioversion ("pill-in-pocket" approach) in athletes with structurally normal hearts.They should not be used as monotherapy.Side effects include atrial flutter and atrial tachycardia with rapid ventricular response. 50Disopyramide (class Ia) is effective in vagal and bradycardia-dependent AF but is now rarely used because of its strong anticholinergic and proarrhythmic effects. 50 patients with sporadic AF, class I drugs may be considered only for acute cardioversion, that is, as a "pill-in-the-pocket" approach.
These patients should refrain from sports as long as AF persists, and until two half-lives of the antiarrhythmic drug have passed. 1

| CATHETER ABLATION
Catheter ablation and isolation of the pulmonary veins is effective and can potentially allow return to full competitive sports activities.
This was the successful treatment of our patients #2 and #3.Athletes with persistent symptomatic AF who have failed or are intolerant to medical therapy should be referred for AF ablation.In Addition, AF ablation should be considered first-line therapy in individuals in whom tachycardia-induced cardiomyopathy is suspected, 24 such as our patient #3.Despite the cardiac remodeling that occurs in athletes, AF ablation has been shown to be effective.Prasitlumkum et al. presented data from nine observational studies with a total of 1129 participants undergoing AF ablation, of whom 51% were endurance athletes. 51The rate of atrial arrhythmia recurrences following AF catheter ablation was similar between endurance T A B L E 2 Summary of key treatment options available to athletes with atrial fibrillation [adapted from ref. 13 ].sporting activity at a time when the lowest DOAC concentration is reached after intake.This strategy is able to minimize competitionrelated hemorrhagic risk and, at the same time, is able to reduce thrombotic risk by shifting the time of anticoagulant resumption to the end of a competition, when the risk of hemorrhagic trauma is practically absent. 53e endurance sport activity individual's preference has to be considered in a complex shared decision-making process.It seems prudent to advise to consider a stepwise approach, starting with a period of detrainingoften disagreed with by the individual-to determine whether AF is associated with exercise or not. 53Prior CHA 2 DS 2 -VASc score and the need for anticoagulant therapy after ablation are other aspects that need to be evaluated, particularly in those practicing contact sports.[53][54][55] In summary, an active and fit lifestyle is better than a sedentary lifestyle and also reduces the AF risk.Data suggests that the risk of developing AF seems to be related to the type and intensity of exercise.Endurance exercise far beyond the recommended amount in current guidelines, seems to be associated with higher AF risk.
Athletes with AF can present with heterogeneous clinical symptoms or being asymptomatic.Although data is lacking, reduction in physical activity should be considered an initial approach in AF athletes.
Symptomatic athletes should undergo medical therapy or be referred for ablation.DOAC, when needed, can be considered in AF athletes.
AF ablation is recommended in exercising individuals with recurrent, symptomatic AF and/or in those who do not want drug therapy, given it impact on athletic performance.
ligaments and the need for surgery.Echocardiography found LV EF of 50−55% with aortic dilatation of 42 mm, normal aortic valve morphology and function, moderate left atrial enlargement and mild MR.Septal thickness was 11 mm.He underwent coronary CT that revealed a suspected LAD lesion and no left atrial thrombus.He was treated successfully with amiodarone and returned to normal sinus rhythm.Coronary angiography revealed a non-significant hemodynamically LAD narrowing.In spite of the low CHA 2 DS 2 VASc score, he was given DOAC for several months after DC cardioversion and amiodarone was continued [CHADS 2 VASC score = 0].No AF returned during follow up.He continues with amiodarone 200 mg one daily and a NOAC.

T A B L E 1
Potential mechanisms and associated sequelae for atrial fibrillation induced by strenuous endurance exercise.Inflammation/Fibrosis Increased vagal tone Regular enhanced sympathetic stimulation during exercise Atrial and Ventricular dilation/hypertrophy Increased stress/shear forces Vagally mediated shortening of the atrial refractory period, atrial stretch, atrial inflammation, scarring Recurrent fluid and electrolyte shifts endurance exercise load on AF burden in athletes with AF remains unexplored.In those with ventricular arrhythmias, there is data to support detraining.Exercise-induced ventricular hypertrophy and dilatation